The basic purposes of the proposed research are to elucidate the biochemical mechanisms which regulate the production and secretion of the plasma lipoprotein lipids by the liver, and therefore regulate, in part, the concentration of plasma lipids. Plasma lipoprotein lipids to a large extent result from hepatic metabolism of free fatty acids (FFA); we therefore propose to continue our studies on the metabolism of FFA by the isolated perfused rat liver to (1) compare the relationships between output of triglyceride, oxidation of FFA, and accumulation of triglyceride in the liver and cholesterogenesis, (2) study effects of substrate (saturated vs. unsaturated FFA) on output of triglyceride and other lipid classes in the very low density lipoprotein (VLDL), (3) investigate effects of nutritional state, sex, hormones (thyroid hormones, sexual steroids, adrenal steroids, cyclic AMP), drugs, and toxic agents on the formation, secretion, properties and composition of the VLDL, VLDL lipids and apoprotein, (4) study effects of FFA substrate, hormones, and drugs on fatty acid-stimulated secretion and biosynthesis of cholesterol by the liver. An equally important second purpose of the proposed work is to relate the observations obtained with the perfused liver to the intact animals. We therefore propose to determine whether the effects of dietary fatty acids on the composition and concentration of plasma lipoprotein lipids, particularly the VLDL, in man and rat in vivo can be explained in part by the directive influence of FFA on hepatic production of VLDL lipids, as observed in vitro. If effects of diet on blood lipids can be explained in part by substrate regulation of the formation and secretion of plasma lipoprotein (particularly VLDL) lipids, we will have a more rational understanding of the nature and control of hyperlipidemia.